Structural protein defect linked to sudden death risk

For about one-fourth of people with an inherited heart problem called long QT syndrome, the source of their problem was a mystery – until researchers at Baylor College of Medicine, the Texas Heart Institute and Texas Children's Hospital in Houston pinpointed a defect in a structural protein in a report in current edition of the journal Circulation: Arrhythmia and Electrophysiology.

A mutation in a cytoskeletal protein called alpha-1-synotrophin, one of the molecules that helps heart cells maintain their shape, changes the functioning of a tiny pore called a sodium ion channel, resulting in long QT syndrome in at least a portion of these patients, said Dr. Matteo Vatta, assistant professor of paediatrics - cardiology at BCM and associate director of paediatric cardiac research. Vatta is senior author of the report.

Until now, defects in genes for particular ion channels have been blamed for inherited long QT syndrome, said Vatta. However, experts could identify no defects in about 25 percent of people with the problem.

Ions are charged chemicals such as sodium or potassium that flow in and out of pores called channels in the cell membranes. The channels open and close in a specific sequence, letting the chemicals in and out of cell in a manner that prompts them to beat in synchrony. When the cells can beat in unison, the heart pumps blood. If the ion channels are defective, it affects the beating of the cells and the heart – often with devastating effects. Untreated long QT syndrome can cause the heart to stop suddenly.

"The mutation in this kind of protein called alpha-1-syntrophin is the first associated with long QT syndrome," said Vatta. Previously, he and colleagues had identified a link between long QT syndrome and a defect in caveolin-3, a scaffolding protein.

"I am interested in the connection between the structural and the electrical part of the heart," said Vatta, whose lab is based in the Feigin Center of Texas Children's. "It could have everything to do with susceptibility to arrhythmias (heart rhythm disruptions) in patients with heart disease. First, we had to prove that the structural part of the heart could be involved in electrical problems."

The caveolin-3 finding led to studies of syntrophin, a protein connected to dystrophin, which when mutated causes Duchenne and Becker muscular dystrophy as well as the X-linked form of cardiomyopathy. As people with Duchenne and Becker muscle-wasting disease age, they develop cardiomyopathy, a weakening of the heart muscle, with heart rhythm disruptions called arrhythmias. This leads to heart failure and an increased risk of sudden cardiac death (sudden heart stoppage) caused by the arrhythmias.

"Syntrophin is the bridge that connects dystrophin to the sodium channel," said Vatta. Dystrophin is critical in the binding of syntrophin to the sodium channel, he said. A mutation in syntrophin disrupts the proper functioning of the sodium channel.

That leads to an electrical problem that disrupts the normal beating of the heart, he said. The finding is proof of the concept that patients with mutations in the structural part of the heart muscle cells also have a problem with how the electrical system of the heart works, leading to dysrhythmias.

"Once you screen all the ion channels and do not find changes that can lead to a pathological effect such as long QT syndrome, then you have to think about all the proteins that interact with the ion channels," Vatta said.

(Source: Arrhythmia and Electrophysiology: Baylor College of Medicine: July 2008)